Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.

INTRODUCTION/BACKGROUND: Published studies on association of germline monogenic genes and lung cancer risk were inconsistent. Our objective is to assess the validity of reported candidate monogenic genes for their association with lung cancer. MATERIALS AND METHODS: A systematic review of published papers prior to August 2022 was performed first to identify all genes where germline mutations were associated with lung cancer risk. We then performed a confirmation study in 2,050 lung cancer cases and 198,553 controls in the UK Biobank (UKB). Germline mutations of these genes were identified from sequencing data and annotated using The American College of Medical Genetics criteria. The robust SKAT-O, a gene-based analysis that properly controls for false positives due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, and genetic background. RESULTS: The systematic review identified 12 genes that were statistically significantly associated with lung cancer risk in at least one study (P < .05), including ATM, BLM, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, MSH6, PMS1, RAD51C, RAD51D, and TP53. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for ATM (P = 4.47E-4) at the study-wise significance level (P < .0042, Bonferroni correction for 12 tests). Suggestive evidence of association was found for 2 other genes, BRCA2 (P = .007) and TP53 (P = .03). Among these 3 genes, the lung cancer risks range from 1.95 (BRCA2) to 5.28 (TP53). CONCLUSION: This study provides statistical evidence for association of previously reported genes and lung cancer risk and has clinical utility for risk assessment and genetic counseling.

National guideline concordance and outcomes for pathologic N2 disease in non-small cell lung cancer.

Background: Real-world treatment practices for positive mediastinal nodal disease in non-small cell lung cancer (NSCLC) continues to vary despite guidelines. We aim to assess national trends in the treatment of pathologic-N2 disease, and evaluate the association with clinical nodal staging and timing of systemic therapy. Methods: The National Cancer Database was queried for patients with NSCLC who underwent lobectomy and had pathologic-N2 disease from 2010-2017. National Comprehensive Cancer Network (NCCN) guideline concordance was evaluated. cN2 patients were analyzed based on timing of systemic therapy and response. Multivariable logistic regression evaluated outcomes by type of systemic therapy. Survival analysis utilized Cox proportional hazards regression and Kaplan-Meier methods. Results: 10,225 patients met inclusion criteria. Fifty-four percent of patients were understaged prior to surgery as either cN0 or cN1. Of clinically staged N2 patients, 56% received NCCN recommended neoadjuvant therapy. Annual guideline concordance increased until 2016 to a max of 62.9%. Neoadjuvant and adjuvant systemic therapy showed an overall survival benefit compared with no systemic therapy (HR 0.54 & 0.57), but no difference when compared against each other. Complete response after neoadjuvant therapy was associated with improved survival (5-year OS 56.1%, P<0.001), while partial response, no-response, and adjuvant therapy were similar. All systemic treatment strategies improved survival compared with no systemic therapy (5-year OS 24.5%). Conclusions: Guideline concordance for treatment of cN2 disease has been increasing, but still not followed in over 1/3 of patients. Responsiveness to neoadjuvant therapy appears to be a predictor of survival, and may become a prognostic adjunct for determining which patients would benefit from additional systemic therapy.

Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non-small cell lung cancer.

Objective: To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non-small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes. Methods: Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk-associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression. Results: We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114). Conclusions: The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

BACKGROUND: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation. METHODS: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation. RESULTS: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein. CONCLUSIONS: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

Invasive Mediastinal Staging for Lung Cancer by The Society of Thoracic Surgeons Database Participants.

BACKGROUND: Prior studies suggest underutilization of invasive mediastinal staging for lung cancer. We hypothesized that The Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD) participants would have higher rates of invasive staging compared with previous reports. METHODS: We conducted a retrospective cohort study (2012 to 2016) of lung cancer patients staged by computed tomography and positron-emission tomography and first treated with an anatomic resection. We defined invasive staging by the use of mediastinoscopy, endosonography, or thoracoscopy. Standardized incidence ratios were used to compare participant-level rates of invasive staging, and Poisson regression was used to identify factors associated with invasive staging. RESULTS: Among 29,015 patients across 256 participating STS-GTSD sites, 34% (95% confidence interval: 33% to 34%) underwent invasive staging. The overall rate of invasive staging did not change between 2012 and 2016 (p trend = 0.16). Increasing clinical stage and features suggestive of a central tumor were associated with invasive staging (p < 0.001). Rates of invasive staging among patients with clinical stage IB or greater or features suggestive of a central tumor were 43% (95% confidence interval: 42% to 44%) and 52% (95% confidence interval: 50% to 54%), respectively. There was a more than 40-fold variation in rates of invasive staging across 251 centers contributing at least 10 cases (standardized incidence ratio: lowest = 0.08; highest = 3.26); 66 sites (26%) performed invasive mediastinal staging less often than average and 77 sites (31%) performed invasive staging more often than average. CONCLUSIONS: The STS-GTSD participants performed invasive mediastinal staging more frequently than prior reports, and yet only in a minority of patients. Rates of invasive mediastinal staging vary widely across STS-GTSD participants.

Surgical quality of wedge resection affects overall survival in patients with early stage non-small cell lung cancer.

OBJECTIVES: Very few studies have examined the quality of wedge resection in patients with non-small cell lung cancer. Using the National Cancer Database, we evaluated whether the quality of wedge resection affects overall survival in patients with early disease and how these outcomes compare with those of patients who receive stereotactic radiation. METHODS: We identified 14,328 patients with cT1 to T2, N0, M0 disease treated with wedge resection (n = 10,032) or stereotactic radiation (n = 4296) from 2005 to 2013 and developed a subsample of propensity-matched wedge and radiation patients. Wedge quality was grouped as high (negative margins, >5 nodes), average (negative margins, ≤5 nodes), and poor (positive margins). Overall survival was compared between patients who received wedge resection of different quality and those who received radiation, adjusting for demographic and clinical variables. RESULTS: Among patients who underwent wedge resection, 94.6% had negative margins, 44.3% had 0 nodes examined, 17.1% had >5 examined, and 3.0% were nodally upstaged; 16.7% received a high-quality wedge, which was associated with a lower risk of death compared with average-quality resection (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], 0.67-0.82). Compared with stereotactic radiation, wedge patients with negative margins had significantly reduced hazard of death (>5 nodes: aHR, 0.50; 95% CI, 0.43-0.58; ≤5 nodes: aHR, 0.65; 95% CI, 0.60-0.70). There was no significant survival difference between margin-positive wedge and radiation. CONCLUSIONS: Lymph nodes examined and margins obtained are important quality metrics in wedge resection. A high-quality wedge appears to confer a significant survival advantage over lower-quality wedge and stereotactic radiation. A margin-positive wedge appears to offer no benefit compared with radiation.

Neoadjuvant Chemoradiation Shows No Survival Advantage to Chemotherapy Alone in Stage IIIA Patients.

BACKGROUND: For operable patients with clinical stage IIIA non-small cell lung cancer, the optimum neoadjuvant treatment strategy remains unclear. Our aim was to compare perioperative and long-term outcomes for patients receiving neoadjuvant chemoradiotherapy (NCRT) versus neoadjuvant chemotherapy (NCT) alone. METHODS: We queried the National Cancer Database to identify all patients with N2 and either T1-T2 non-small cell lung cancer who received either NCRT or NCT followed by lobectomy between 2006 and 2012. Patients with T3 tumors were excluded. A propensity match analysis was performed incorporating preoperative variables, and the incidence of postoperative complications, pathologic downstaging, and long-term survival were compared. RESULTS: In all, 1,936 patients met criteria, 745 NCT and 1,191 NCRT. The NCRT patients were younger, less likely to be treated at an academic medical center, and more likely to have adenocarcinoma. After propensity matching, patients in the NCT group showed lower 30-day mortality (1.3% versus 2.9%) and 90-day mortality (2.9% versus 6.0%), and were more likely to undergo a minimally invasive resection (25.7% versus 14.1%). The NCRT patients were more likely to have a pathologic complete response (14.2% versus 4.0%) and to be N0 at the time of resection (45.2% versus 38.7%). In the multivariable analysis, NCRT patients were at a greater risk of mortality than NCT patients (hazard ratio 1.18, 95% confidence interval: 1.03 to 1.36). CONCLUSIONS: In our cohort, combined neoadjuvant chemotherapy and radiation therapy was associated with improved pathologic downstaging but showed increased perioperative mortality with no improvement in long-term overall survival. For stage IIIA patients with smaller tumors without local invasion, chemotherapy alone may be the preferred neoadjuvant treatment.

Predictors of pathologic upstaging in early esophageal adenocarcinoma: Results from the national cancer database.

BACKGROUND: Upstaging in early esophageal adenocarcinoma (EAC) patients happens at a high rate and has implications for treatment. We sought to identify risk factors predicting upstaging. STUDY DESIGN: The National Cancer Database (2010-2013) was queried for all patients with clinical T1/T2 and N0 EAC who underwent esophagectomy without neoadjuvant therapy. Logistic regression models were developed to investigate risk factors for upstaging. RESULTS: A total of 1120 patients were included. Pathologic upstaging occurred in 21.3% (n = 239). After adjustment, risk of upstaging increased with tumor size (tumor size 1-3 cm, OR 4.57,95% CI 2.58-8.10, tumor size >3 cm, OR 10.57, 95% CI 5.77-19.35, as compared to tumors <1 cm) as well as with positive margins (OR 4.13, 95% CI 2.17-7.87) and > than 10 lymph nodes examined (OR 1.85, 95% CI 1.29-2.63), while facility volume was not significant. Odds of upstaging increased linearly with number of lymph nodes examined (OR 1.02 per node). CONCLUSION: Our data underscore the importance of tumor size as a predictor for upstaging and of completing a thorough lymph node dissection for staging purposes.

Improved Lymph Node Staging in Early-Stage Lung Cancer in the National Cancer Database.

BACKGROUND: Lymph node assessment for non-small cell lung cancer (NSCLC) shows wide variation among centers. Our aim was to assess the quality of lymph node assessment in early-stage NSCLC and determine whether any factors are associated with improved lymph node harvest. METHODS: We queried the National Cancer Database to identify patients with clinical stage I NSCLC who underwent segmentectomy or lobectomy between 2004 and 2013. Patients were stratified into three groups (≤5, 6 to 15, and >15) based on the number of lymph nodes assessed. RESULTS: Patients (n = 51,358) met criteria, and mean lymph nodes assessed increased from 8.1 to 10.0 (p < 0.001) over the study period. There was a significant decrease in the percentage of patients with 0 to 5 nodes assessed (41.1% versus 31.1%, p < 0.001) and a significant increase in patients with more than 15 nodes assessed (10.1% versus 17.0%, p < 0.001). Patients at academic centers were less likely to have only 0 to 5 nodes assessed (27.2% versus 43.6% for community, p < 0.001). Variables associated with more than 15 nodes assessed were increasing year, age older than 65 years, male sex, non-African American race, academic centers, lobectomy, and clinical T2 disease. Patients with more than 14 nodes assessed demonstrated more nodal upstaging (17.9% versus 10.9% for 1 to 14 nodes, p < 0.001). Multivariable analysis suggests that at least 14 nodes should be assessed to maximize the probability that node-positive patients are correctly identified. CONCLUSIONS: Lymph node assessment has improved since 2004 but varies by facility type and other characteristics. In our analysis removing at least 14 nodes was associated with more accurate staging.

Tracheal Resection With Carinal Reconstruction for Squamous Cell Carcinoma.

Surgical resection is the treatment of choice for primary malignancies of the trachea. We present here the rare case of a lifelong nonsmoker with primary squamous cell carcinoma of the trachea, requiring tracheal resection and anterior carinal reconstruction. Patient preparation, surgical technique, and considerations to avoid airway anastomotic complications are discussed.

Health risks from computed tomographic screening.

Results of the recent National Lung Cancer Screening Trial show a significant survival benefit for annual screening with a low-dose computed tomographic (CT) scan in high-risk individuals. This result has led the US Preventive Services Task Force to recommend annual low-dose CT scans for this at-risk population. Less well characterized are the risks from screening. The primary risks from screening are radiation exposure, false-positive results and unnecessary diagnostic and therapeutic procedures, overdiagnosis and overtreatment, and increased psychological distress. This article reviews these risks, which must be considered and weighed against the benefits when discussing enrollment with patients.

Subacute endocarditis of an atrial septal closure device in a patient with a patent foramen ovale.

The role of transcatheter closure of a patent foramen ovale for cryptogenic stroke remains controversial. The most common complications include atrial arrhythmia and bleeding. Infectious complications are exceedingly rare. We describe a 37-year-old man with a history of transient ischemic attacks and a patent foramen ovale who underwent transcatheter closure, complicated by subacute endocarditis of the completely endothelialized device 2 years after placement.